The peroxisome proliferator-activated receptors (PPARs) comprise a subfamily of the nuclear receptor superfamily. Four closely related isoforms have been identified and cloned and are commonly known as PPARalpha, PPARgamma-1, PPARgamma-2 and PPARdelta. Each receptor subtype has a signature DNA binding domain (DBD) and a ligand-binding domain (LBD), both being necessary for ligand activated gene expression. PPARs bind as heterodimers with a retinoid X receptor. See J. Berger and D. E. Miller, Annu. Rev. Med., 2002, 53, 409-435.
PPARdelta (also known as PPARbeta) is expressed in a broad range of mammalian tissue, but little information regarding its biological functions or the full array of genes regulated by the receptor have been elucidated. However, it has recently been found that agonists may be useful to treat conditions such as dyslipedemia and certain dermatological conditions, while antagonists may be useful to treat osteoporosis or colorectal cancer (D. Sternbach, in Annual Reports in Medicinal Chemistry, Volume 38, A. M. Doherty, ed., Elsevier Academic Press, 2003 pp. 71-80).
PPARdelta appears to be significantly expressed in the CNS; however much of its function there still remains undetermined. Of singular interest however, is the discovery that PPARdelta was expressed in rodent oligodendrocytes, the major lipid producing cells of the CNS (J. Granneman, et al., J. Neurosci. Res., 1998, 51, 563-573). Moreover, it was also found that a PPARdelta selective agonist was found to significantly increase oligodendroglial myelin gene expression and myelin sheath diameter in mouse cultures (I. Saluja et al., Glia, 2001, 33, 194-204). Thus, PPARdelta activators may be of use for the treatment of demyelinating and dysmyelinating diseases.
Demyelinating conditions are manifested in loss of myelin—the multiple dense layers of lipids and protein which cover many nerve fibers. These layers are provided by oligodendroglia in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS). In patients with demyelinating conditions, demyelination may be irreversible; it is usually accompanied or followed by axonal degeneration, and often by cellular degeneration. Demyelination can occur as a result of neuronal damage or damage to the myelin itself—whether due to aberrant immune responses, local injury, ischemia, metabolic disorders, toxic agents, or viral infections (Prineas and McDonald, Demyelinating Diseases. In Greenfield's Neuropathology, 6.sup.th ed. (Edward Arnold: New York, 1997) 813-811, Beers and Berkow, eds., The Merck Manual of Diagnosis and Therapy, 17.sup.th ed. (Whitehouse Station, N.J.: Merck Research Laboratories, 1999) 1299, 1437, 1473-76, 1483).
Central demyelination (demyelination of the CNS) occurs in several conditions, often of uncertain etiology, that have come to be known as the primary demyelinating diseases. Of these, multiple sclerosis (MS) is the most prevalent. Other primary demyelinating diseases include adrenoleukodystrophy (ALD), adrenomyeloneuropathy, AIDS-vacuolar myelopathy, HTLV-associated myelopathy, Leber's hereditary optic atrophy, progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis, Guillian-Barre syndrome and tropical spastic paraparesis. In addition, there are acute conditions in which demyelination can occur in the CNS, e.g., acute disseminated encephalomyelitis (ADEM) and acute viral encephalitis. Furthermore, acute transverse myelitis, a syndrome in which an acute spinal cord transection of unknown cause affects both gray and white matter in one or more adjacent thoracic segments, can also result in demyelination. Also, disorders in which myelin forming glial cells are damaged including spinal cord injuries, neuropathies and nerve injury.
Selective PPARdelta modulators may also be useful for treating or preventing other disease states see, for example, Joel Berger et al., Annu. Rev. Med. 2002, 53, 409-435; Timothy Wilson et al. J. Med. Chem., 2000, Vol. 43, No. 4, 527-550; Steven Kliewer et al., Recent Prog Horm Res. 2001; 56: 239-63; Jean-Charles Fruchart, Bart Staels and Patrick Duriez: PPARS, Metabolic Disease and Arteriosclerosis, Pharmacological Research, Vol. 44, No. 5, 345-52; 2001; Sander Kersten, Beatrice Desvergne & Walter Wahli: Roles of PPARs in health and disease, Nature, vol 405, 25 May 2000; 421-4; Ines Pineda Torra, Giulia Chinetti, Caroline Duval, Jean-Charles Fruchart and Bart Staels: Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice, Curr Opin Lipidol 12: 2001, 245-254).
Compounds acting as PPARdelta modulators may be particularly suitable for the treatment and/or prevention of disorders of fatty acid metabolism and glucose utilization disorders in which insulin resistance is involved. These include diabetes mellitus, especially type-2 diabetes, including the prevention of dyslipidemia and the sequelae associated therewith. More specifically, PPARdelta modulators may also be used to treat hyperglycemia, they may be useful in the improvement in insulin resistance, their use may show an improvement in glucose tolerance, the protection of the pancreatic β cells, as well as the prevention of macro- and microvascular disorders.
Dyslipidemias and their sequelae, treatable with the use of PPARdelta modulators are for example, atherosclerosis, coronary heart disease, cerebrovascular disorders etc, especially those (but not restricted thereto) which are characterized by one or more of the following factors:
high plasma triglyceride concentrations, high postprandial plasma triglyceride concentrations, low HDL cholesterol concentrations, low ApoA lipoprotein concentrations, high LDL cholesterol concentrations, small density LDL cholesterol particles, high ApoB lipoprotein concentrations and mixtures thereof.
Various other conditions which may be associated with the metabolic syndrome, such as: obesity (excess weight), including central obesity, thromboses, hypercoagulable and prothrombotic states (arterial and venous), high blood pressure, heart failure such as, for example (but not restricted thereto), heart attack or stroke following myocardial infarction, hypertensive heart disease or cardiomyopathy.
Other disorders or conditions in which inflammatory reactions or cell differentiation, may for example be involved are: atherosclerosis such as, for example (but not restricted thereto), coronary sclerosis including angina pectoris or myocardial infarction, stroke, vascular restenosis or reocclusion, chronic inflammatory bowel diseases, such as, for example, Crohn's disease and ulcerative colitis, pancreatitis, other inflammatory states, retinopathy, adipose cell tumors, lipomatous carcinomas such as, for example, liposarcomas, solid tumors and neoplasms such as, for example (but not restricted thereto), carcinomas of the gastrointestinal tract, of the liver, of the biliary tract and of the pancreas, endocrine tumors, carcinomas of the lungs, of the kidneys and the urinary tract, of the genital tract, prostate carcinomas etc., acute and chronic myeloproliferative disorders and lymphomas angiogenesis, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, erythemato-squamous dermatoses such as, for example, psoriasis, acne vulgaris.
Other skin disorders and dermatological conditions modulated by PPARdelta agonists include eczemas and neurodermitis, dermatitis such as, for example, seborrheic dermatitis or photodermatitis, keratitis and keratoses such as, for example, seborrheic keratoses, senile keratoses, actinic keratosis, photo-induced keratoses or keratosis follicularis keloids and keloid prophylaxis, warts, including condylomata or condylomata acuminata, human papilloma viral (HPV) infections such as, for example, venereal papillomata, viral warts such as, for example, molluscum contagiosum, leukoplakiapapular dermatoses such as, for example, Lichen planus, skin cancer such as, for example, basal-cell carcinomas, melanomas or cutaneous T-cell lymphomas, localized benign epidermal tumors such as, for example, keratoderma, epidermal naevi and chilblains.
Various other conditions potentially modulated by PPARdelta including syndrome X, polycystic ovary syndrome (PCOS), asthma osteoarthritis, lupus erythematosus (LE) or inflammatory rheumatic disorders such as, for example, rheumatoid arthritis, vasculitis, wasting (cachexia), gout ischemia/reperfusion syndrome and acute respiratory distress syndrome (ARDS).